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BEHAVIOURAL 
BRAIN 
RESEARCH 

Behavioural Brain Research 73 ( 1996) 121-124 SSSSSSSS 



Human psychopharmacology of N,N-dimethyltryptamine 

Rick J. Strassman* 

Department of Psychiatry, University of New Mexico, Albuquerque, NM 87131-5326 USA 




ELSEVIER 



Abstract 

We generated dose-response data for the endogenous and ultra-short-acting hallucinogen, N,N-dimethyltryptamine (DMT), in 
a cohort of experienced hallucinogen users, measuring multiple biological and psychological outcome measures. Subjective 
responses were quantified with a new rating scale, the HRS, which provided better resolution of dose effects than did the biological 
variables. 

A tolerance study then was performed, in which volunteers received four closely spaced hallucinogenic doses of DMT. Subjective 
responses demonstrated no tolerance, while biological measures were inconsistently reduced over the course of the sessions. Thus, 
DMT remains unique among classic hallucinogens in its inability to induce tolerance to its psychological effects. 

To assess the role of the 5-KT 1A site in mediating DMT's effects, a pindolol pre-treatment study was performed. Pindolol 
significantly increased psychological responses to DMT, suggesting a buffering effect of 5-HT lj4 agonism on 5-HT 2 -mediated 
psychedelic effects. These data are opposite to those described in lower animal models of hallucinogens' mechanisms of action. 



1. Introduction 

Human research with hallucinogenic drugs was 
severely curtailed by the passage of the Controlled 
Substances Act of 1970 [21]. Nearly a generation 
elapsed before a renewal of clinical studies occurred in 
the United States and Europe. These studies have begun 
to address gaps in basic understanding of effects and 
mechanisms of action created by this hiatus, during 
which many of the standard methods of psychopharma- 
cology and psychotherapy research were developed. 

There are several reasons why the careful study of 
hallucinogens has relevance to psychiatric research. 

(1) The clinical syndrome elicited by hallucinogens 
affects all of the mental functions associated with human 
consciousness, including mood, perception, cognition, 
self-control and somatic awareness [5]. Generating 
mechanistic hypotheses based upon systematic data col- 
lection will provide insights into many basic brain-mind 
relationships. 

(2) Use and abuse of hallucinogens among young 
adults is increasing [10,11], with an attendant rise in 
emergency room and psychiatric clinic utilization for 
assessment and treatment of adverse effects [7]. There 
is a need to understand how best to treat hallucinogen- 
elicited psychiatric disorders quickly, safely, and effec- 



* Corresponding author. 



tively, in addition to providing accurate information to 
clinicians regarding effects and sequelae of hallucinogen 
use and abuse. 

(3) The degree of overlap between endogenous psycho- 
ses and hallucinogenic drug inebriation has been debated 
vigorously [8,12]. The appellations 'psychotogen' and 
'psychotomimetic' bespeak early efforts to relate the two 
syndromes. Similarities appear to be greatest during 
acute phases of schizophrenia [2]. Short-chain tryptam- 
ines remain attractive candidates for naturally occurring 
psychotogens [3]. Current interest in mixed 5-HT 2 /DA 2 
antagonists as anti-psychotic agents [14] also under- 
scores the importance of studying 5-HT 2 -active halluci- 
nogens as models for endogenous psychoses. 

(4) The ability of hallucinogens to enhance the psy- 
chotherapeutic process was an area of intense interest 
during the first phase of hallucinogen research [17]. 
Restrictions on human use of these drugs prevented 
necessary clarification regarding with whom, and how 
best to utilize these drugs within a psychotherapeutic 
context. Recent advances in psychotherapy research [24] 
suggest models by which a more careful and systematic 
approach to combining hallucinogen drug administra- 
tion with well-characterized forms of psychotherapy 
may proceed. 

We have been investigating effects and mechanisms 
of action of the short-chain tryptamine, ultra-short- 
acting endogenous hallucinogen, N,N-dimethyltrypta- 



0166^328/96/59.50 © Elsevier Science B.V. All rights reserved 
SSSDI 0166-4328(96)00081-X 



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Rick J. Strassman/ Behavioural Brain Research 73 ( 1996) 121-124 



mine (DMT), in a cohort of experienced hallucinogen 
users since November, 1990. Three reasons prompted 
choosing DMT as the compound with which to renew 
clinical research with hallucinogens. First, it is extremely 
short-acting [18], and adverse effects which might occur 
in a busy clinical research unit would be easier to 
manage. Second, it is a naturally occurring hallucinogen 
[ 1 ], whose role in normal and abnormal mental processes 
has yet to be explicated adequately. Third, its relative 
obscurity would not draw undue attention to our work 
in the early delicate stages of resuming this research, 
relative to the certain flurry of interest that a better 
known hallucinogen, such as LSD, might. 

We chose to study experienced hallucinogen users for 
the following reasons: experienced users would be less 
likely to panic during the powerful hallucinogenic effects 
expected from DMT; they would be able to provide 
more detailed accounts of DMT effects, particularly 
relative to other better known compounds, such as LSD 
and psilocybin, than naive subjects; finally, liability for 
development of subsequent 'drug abuse' would be less 
likely to be sustained in previous or current users. 

2. Summary of experiments and results 

Each of the three studies to be described utilized 
male and female experienced hallucinogen users who 
were otherwise medically and psychiatrically healthy. 
Screening was rigorous, and included a medical history, 
physical examination, electrocardiogram, urinalysis, 
complete blood count, 24-item chemistry panel, and 
thyroid functions. Subjects were excluded who were 
taking any medication regularly, or who had a history 
of high blood pressure. Psychiatric screening included a 
semi-structured psychiatric interview, the Structured 
Clinical Interview for DSM-III-R, Outpatient [20], and 
a survey of drug use history. Those with current drug 
abuse problems or history of psychosis were excluded. 
If volunteers had a history of a major depressive episode, 
they were included if the depression had resolved at 
least two years before beginning the study, and they 
were not in stressful life circumstances conducive to a 
relapse. In addition, if volunteers had not had what the 
research team considered 'full-blown' experiences on 
hallucinogenic drugs, they were not enrolled, as we 
wanted to ensure that volunteers could manage the 
highly intoxicated state of a high-dose DMT session. 

Studies all took place in the inpatient unit of the 
University of New Mexico Hospital Clinical Research 
Center. Prospective volunteers first received low 
(0.05 mg/kg) and high (0.4 mg/kg) screening doses of 
intravenous (i.v.) DMT fumarate, non-blind, to familiar- 
ize themselves with the research setting, provide an 
opportunity to drop out before extensive data were 
collected, and for idiosyncratic hypertensive responses 



to the low dose to be noted and exclude further 
participation. 

Our first dose-response study utilized 0.05, 0.1, 0.2 
and 0.4 mg/kg i.v. DMT fumarate, and saline placebo, 
in a double-blind, randomized design, using 12 volun- 
teers. These results have been published [22,23]. A new 
rating scale for hallucinogen effects, the Hallucinogen 
Rating Scale (HRS), was developed, which clustered 
responses into six clinical categories: Affect, Volition, 
Somatic Effects ('Somaesthesia'), Perception, Cognition, 
and Intensity. Biological measures included: heart rate 
(HR), mean arterial blood pressure (MAP), pupil diame- 
ter, core temperature; and adrenocorticotropin (ACTH), 
/i-endorphin (/?E), prolactin (PRL), growth hormone 
(GH), melatonin, Cortisol and DMT-free base blood 
levels. The 'psychedelic' threshold for DMT was at 
0.2 mg/kg, at which most biological effects also demon- 
strated statistically significant differences from saline 
placebo. Only melatonin showed no stimulation by 
DMT, while GH levels, although stimulated, could not 
be differentiated by dose. Pupil diameter, HR, MAP, 
ACTH, /?E, DMT, and subjective responses all peaked 
within 2 min; PRL and Cortisol responses lagged by 
5-15 min, while temperature and growth hormone eleva- 
tions did not begin until psychological effects had 
resolved, by 15-20 min. 

Psychological effects began nearly immediately during 
the DMT infusion, peaked within 2 min, and usually 
were completely resolved within 30 min. The higher 
doses of DMT produced a rapidly moving, multi-dimen- 
sional, kaleidoscopic display of intensely colored abstract 
and representational images. Auditory effects were less 
common, and were not frank hallucinations. Transient 
anxiety was common, but usually quickly became 
replaced by euphoria. Dissociation of awareness from 
the physical body was common, as were later feelings of 
alternating heat and cold. The higher dose effects com- 
pletely replaced ongoing mental experience, and usually 
was described as more compelling and convincing than 
'ordinary' reality or dreams. Lower doses (0.1 and 
0.05 mg/kg) primarily affected physical and affective 
functions, with little perceptual disturbances. HRS data 
were more capable of distinguishing between dose levels 
(e.g., between 0.1 and 0.05 mg/kg) than were biological 
data. These data were interpreted in the light of 
5-HT mechanisms, especially 5-HT 2 and 5-HT lx site 
activation. 

More experimental studies were then designed, the 
first being an assessment of DMT's ability to induce 
tolerance to its biological and psychological effects. 
Previous attempts in humans had failed to elicit toler- 
ance [6], while heroic efforts in lower animals were 
required to do so [13]. 

A fully hallucinogenic dose, 0.3 mg/kg, of i.v. DMT 
fumarate, or saline placebo, was administered at half- 
hour intervals, 4 times in a morning, to 1 3 experienced 



Rick J. Strassman/ Behavioural Brain Research 73 (1996) 121-124 



123 



hallucinogen-using volunteers. Neither clinical inter- 
views nor HRS results demonstrated development of 
psychological tolerance. HR decreased from the first to 
second session, and did not change thereafter, suggesting 
'reduction of anticipatory anxiety,' rather than 'toler- 
ance;' while no reduction in MAP was seen. ACTH and 
PRL responses did decrease over the course of the 
morning, suggesting tolerance development. This 
differential tolerance development was interpreted as 
being mediated by independently regulated desensitiza- 
tion of relevant 5-HT receptor mechanisms. Thus, DMT 
remains unique in its inability to develop tolerance to 
its psychological effects. 

Our last study completed assessed the role of the 
5-HT 1j4 site in mediating DMT effects. This was per- 
formed because DMT has nearly equal affinity for the 
5-HT 1A and 5-HT 2 sites [4], and the behavioral effects 
of the hallucinogen 5-methoxy-DMT are blocked by 
pindolol [19], a potent 5-HT lA antagonist [16]. 

Twelve volunteers received a sub-hallucinogenic dose, 
0. 1 mg/kg, i.v. DMT, or saline placebo, in combination 
with 30 mg oral racemic pindolol, or placebo-pindolol, 
in a four-cell double-blind, randomized design. 
Volunteers found that pindolol pre-treatment enhanced 
DMT effects by two to three times, which was substanti- 
ated by scores on the HRS, in which four to six clinical 
clusters demonstrated a significant enhancement by pin- 
dolol. PRL responses were reduced, while those of 
ACTH were unaffected. HR responses were blunted, 
probably due to pindolol's anti-sympathetic effects, 
while MAP effects were enhanced. These behavioral 
data, opposite to those noted in the animal literature, 
suggest an inhibitory effect of 5-HT M agonism in tryp- 
tamine-induced hallucinogenesis. Pindolol blockade 
allowed unopposed 5-HT 2 agonism, which we believe 
also mediated the enhanced MAP responses to DMT. 
The reduced PRL response supports a stimulatory role 
for the 5-WY lA site in human PRL secretion, while the 
lack of effect on ACTH suggests a minimal role for this 
site in the DMT response. These data also are important 
because they demonstrate differential (and at times, 
opposite) regulation of neuroendocrine, cardiovascular, 
and subjective effects of hallucinogens in humans. 



3. Conclusions and future directions 

DMT can be safely administered to experienced hallu- 
cinogen users in fully 'psychedelic' doses. By so doing, 
earlier clinical research findings can be extended to 
include contemporary psychopharmacological method- 
ologies, and basic hypotheses tested. In the case of DMT, 
a battery of neuroendocrine data have been generated, 
and a new rating scale developed. The lack of tolerance 
to DMT's psychological effects has been established 
more rigorously, which strengthens its role as a putative 



endogenous 'psychotogen' [9]. Our study of the role of 
the 5-HT 1A site in mediating DMT effects in humans 
has yielded results opposite to those expected from 
animal data. 

Current studies include a pre-treatment protocol using 
the only currently available 5-HT 2 antagonist, cyprohep- 
tadine, which will expand previous human work with 
this combination [15]. In addition, we are beginning to 
develop comprehensive dose-response data for the 
longer-acting, and more widely abused hallucinogen, 
psilocybin ( 4-phosphoryloxy-N,N-DMT ) . 



Acknowledgment 

This investigation was supported by the Scottish Rite 
Foundation for Schizophrenia Research, NMJ; National 
Institute on Drug Abuse grants RO3-DA06524 and 
RO1-DA08096; University of New Mexico General 
Clinical Research Center grant RR00997; the Scott 
Rogers Fund of the University of New Mexico; and 
University of New Mexico Department of Psychiatry 
research funds. The authors would like to thank David 
E. Nichols, Ph.D., Purdue University, for synthesis of 
the DMT fumarate used in this study. 



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